. 2013 Jun 14;11(6):2069–2112. doi: 10.3390/md11062069

Table 1.

Protease inhibitors from venomous animals. Some protease inhibitors with less information about sequence or biological activity, as well as some putative protease inhibitors only found by means of transcriptomic approach but not tested against proteases, were not included in this table (some of them are found within the text, with the respective UniProtKB code). Organisms from which the PIs were obtained are indicated by the symbols at left: # sea anemones; + snakes; § scorpions; ¥ spiders; ¤ Anurans; ø Hymenopterans. Capital letters denote the proteases inhibited: T, trypsin; C, chymotrypsin; CL, cathepsin L; CB, cathepsin B; P, papain; K, kallikrein; PK, plasma kallikrein; TK, tissue kallikrein; Pl, plasmin; E, elastase; nE, neutrophil elastase; pE, pancreatic elastase; X, factor Xa; XII, α-factor XIIa; SA, subtilisin A; ptK, proteinase K; Th, thrombin. Structural classes are indicated by symbols: ♦ Kunitz-type motif protease inhibitors; ▯ Kazal-type protease inhibitors; ● thyroglobulin type-1domain; ◊ Ascaris-type motif; ○ Bowman-Birk-type motif.

Specie	Toxin	UniProt KB	AA ^a	Protease inhibited	Inhibitory activity ^b–g	References
# Actinia equina	♦ AEPI-I	-	59 ^III	-	-	[26]
	♦ AEPI-II	-	59 ^III	-	-	[26]
	● Equistatin	P81439	199 ^III	Cathepsin L *,	0.051 (CL),	[25,43]
				papain,	0.57 (P),
				cathepsin B	1.4 (CB) ^b
	♦ AEAPI	-	57 ^III	Trypsin *, plasmin	700 IU/mg (T) ^c	[24]
# Anemonia sulcata	■ Elastase inhibitor	P16895	48 ^III	Porcine elastase	1.0 ^d	[28,44]
	♦ Kalicludin-1 or AsKC1	Q9TWG0	58 ^III	Trypsin	<30 ^d	[27]
	♦ Kalicludin-2 or AsKC2	Q9TWF9	58 ^III	Trypsin	<30 ^d	[27]
	♦ Kalicludin-3 or AsKC3	Q9TWF8	59 ^III	Trypsin	<30 ^d	[27]
	♦ SA5 II	P10280	62 ^III	Kallikrein, Trypsin	0.3 (T) ^d	[29,32]
# Anthopleura aff. xanthogrammica	♦ AXPI-I or AXAPI	P81547	58 ^III	Trypsin *, chymotrypsin, elastase, thermolysin	1900 IU/mg (T) ^c	[24,41]
# Anthopleura aff. xanthogrammica	♦ AXPI-II	P81548	58 ^III	Trypsin *, chymotrypsin	490 IU/mg (T) ^c	[41]
# Anthopleura elegantissima	♦ APEKTx1	P86862	65 ^III	Trypsin	124 ^d	[42]
# Anthopleura fuscoviridis	♦ AFAPI-I	-	56 ^III	Trypsin *, plasmin	950 IU/mg (T) ^d	[24]
# Anthopleura fuscoviridis	♦ AFAPI-III	-	56 ^III	Trypsin *, plasmin	900 IU/mg (T) ^d	[24]
# Heteractis crispa	♦ Jn-IV	P16344	56 ^III	Trypsin	9.6 ^d	[32,33]
	♦ InhVJ	-	56 ^III	Trypsin *,	2.49 (T),	[45,46,47]
	♦ InhVJ	-	56 ^III	chymotrypsin	21.7 (C) ^d	[45,46,47]
	♦ APHC1	B2G331	56 ^III	Trypsin,	1000 (T),	[34]
	♦ APHC1	B2G331	56 ^III	chymotrypsin	~5000 (C) ^d	[34]
# Rhodactis rhodostoma	♦ Inhibitor 4	-	48 ^II	Trypsin, kallikrein *, chymotrypsin	0.95 (T), 0.49 (K), 33 (C) ^d	[31]
# Stichodactyla haddoni	♦ SHTX-3	B1B5I8	62 ^III	Trypsin	203 IU/mg ^c	[40]
# Stoichactis helianthus	♦ ShPI-1	P31713	55^III	Serine *,	0.11 (T),	[36,37]
				cysteine,	2.3 (C),
				aspartic proteases	2.7 (Pl) ^d
	♦ ShPI-2	P81129	55 ^III	Serine, cysteine, aspartic proteases	n.f.	[38]
+ Dendroaspis polylepis polylepis	♦ Dendrotoxin E	P00984	59 ^III	Trypsin *,	1.0 (T),	[48]
+ Dendroaspis polylepis polylepis	♦ Dendrotoxin E	P00984	59 ^III	chymotrypsin	100 (C) ^d	[48]
+ Daboia siamensis	♦ BBPTI-1	-	60 ^III	Chymotrypsin	4.77 ^b	[49]
	♦ CBPTI-1	A8Y7N4	66 ^III	Trypsin	407 ^b	[50]
	♦ CBPTI-2	A8Y7N5	60 ^III	Trypsin	666 ^b	[50]
	♦ CBPTI-3	A8Y7N6	60 ^III	Chymotrypsin	2.55 ^b	[50]
+ Hemachatus haemachatus	♦ HHV inhibitor II	P00985	57 ^III	Trypsin, chymotrypsin, kallikrein, plasmin	-	[51]
+ Naja nivea	♦ NNV inhibitor II	P00986	57 ^III	Trypsin	-	[51]
+ Vipera ammodytes	♦ Trypsin inhibitor I	P00991	61 ^III	Trypsin *, chymotrypsin, kallikrein, plasmin	0.34 (T), 270 (C) ^b	[52,53]
	♦ Trypsin inhibitor II	-	62 ^III	Trypsin *, chymotrypsin, kallikrein, plasmin	0.56 (T), 300 (C) ^b	[52]
	♦ Chymotrypsin inhibitor	P00992	65 ^III	Chymotrypsin *, trypsin, plasma kallikrein	4.3 (C), 5100 (T) ^b	[52]
+ Bungarus fasciatus	♦ BF9	P25660	65 ^III	Chymotrypsin	58 ^d	[54]
+ Bungarus fasciatus	♦ Bungaruskunin	B2KTG1	59 ^III	Chymotrypsin *, trypsin, elastase	6100 (C) ^b	[55]
+ Naja naja	♦ Trypsin inhibitor	P20229	57 ^III	Trypsin	0.0035 ^b	[56]
+ Naja atra	♦ NACI	Q5ZPJ7	57 ^III	Chymotrypsin	25 ^b	[57,58]
+ Ophiophagus hannah	♦ Oh11-1	P82966	58 ^III	Chymotrypsin	3520 ^b	[59]
	♦ OH-TCI	B6RLX2	58 ^III	Chymotrypsin *,	84.6 (C),	[60]
	♦ OH-TCI	B6RLX2	58 ^III	trypsin	391 (T) ^b	[60]
+ Bungarus multicinctus	♦ PILP-1	B4ESA2	58 ^III	Trypsin	55.62 ^b	[61]
+ Oxyuranus scutellatus scutellatus	♦ TSPI	B7S4N9	62 ^III	Kallikrein *, trypsin, plasmin, elastase, factor Xa, α-factor XIIa	0.057 (PK), 0.23 (TK), 0.31 (T), 6.1 (Pl), 201 (E), 871 (X), 2380 (XII) ^b	[62,63]
+ Pseudonaja textilis textilis	♦ Textilinin-1	Q90WA1	59 ^III	Plasmin *,	0.49 ± 0.02 (Pl),	[7,63]
	♦ Textilinin-1	Q90WA1	59 ^III	trypsin	0.76 ± 0.02 (T) ^b	[7,63]
	♦ Textilinin-2	Q90WA0	59 ^III	Plasmin	2.2 ^b	[7]
+ Macrovipera lebetina transmediterranea	♦ PIVL	I2G9B4	67 ^III	Trypsin	-	[64]
+ Pseudechis australis	♦ Pr-mulgin 1	E7FL11	59 ^III	Metalloprotease 2	60 ^b	[65]
	♦ Pr-mulgin 2	E7FL12	59 ^III	Trypsin *,	5 (T),	[65]
				chymotrypsin,	40 (C),
				plasmin	40 (Pl) ^b
	♦ Pr-mulgin 3	E7FL13	59 ^III	Trypsin,	5 (T),	[65]
	♦ Pr-mulgin 3	E7FL13	59 ^III	plasmin	100 (Pl) ^b	[65]
§ Mesobuthus tamulus	♦ Fraction IX-1-a	-	-	Trypsin *,	19.2 IU/mg (T),	[66]
§ Mesobuthus tamulus	♦ Fraction IX-1-a	-	-	kallikrein	87 IU/mg (K) ^c	[66]
§ Hadrurus gertschi	♦ rHg1	P0C8W3	67 ^III	Trypsin	107 ^d	[67,68]
§ Lychas mucronatus	♦ rLmKTT-1a	P0DJ46	59 ^III	Trypsin	140 ^d	[16,68]
	♦ rLmKTT-1b or SdPI	P0DJ45	59 ^III	Trypsin	160 ^d	[16,68]
	♦ rLmKTT-1c	P0DJ48	59 ^III	Trypsin	124 ^d	[68]
§ Mesobuthus martensii	♦ rBmKTT-1	P0DJ49	59 ^III	Trypsin	136 ^d	[68]
	♦ rBmKTT-2	P0DJ50	58 ^IV	Trypsin	420 ^d	[68]
	♦ rBmKTT-3	P0DJ47	70 ^III	Trypsin	760 ^d	[68]
§ Scorpiops jendeki	◊ rSjAPI	-	64 ^V	Chymotrypsin *,	97.1 (C),	[69]
§ Scorpiops jendeki	◊ rSjAPI	-	64 ^V	elastase	3700 (E) ^b	[69]
¥ Ornithoctonus huwena	♦ HWTX-XI	P68425	55 ^III	Trypsin	0.23 ^d	[14]
¥ Araneus ventricosus	♦ AvKTI	K7YYJ2	57 ^III	Trypsin,	7.34 (T),	[70]
				chymotrypsin,	37.75 (C),
				plasmin *,	4.89 (Pl),
				neutrophil elastase	169.07 (E) ^b
	♦ AvCI	L7X735	70 ^IV	Chymotrypsin,	49.85 (C),	[71]
				subtilisin A,	20.51 (SA),
				proteinase K,	65.42 (ptK),
				neutrophil elastase,	8.74 (nE),
				pancreatic elastase	11.32 (pE) ^b
¤ Bombina bombina	◊ BSTI	Q90248	60 ^V	Trypsin,	80–100 (T),	[72]
¤ Bombina bombina	◊ BSTI	Q90248	60 ^V	thrombin	1300 (Th) ^b	[72]
¤ Bombina maxima	◊ BMTI	Q8QFP3	60 ^V	Trypsin	60 ^b	[73]
¤ Rana areolata	◊ Trypsin inhibitor	-	61 ^V	Trypsin	~20,000 ^e	[74]
¤ Bombina orientalis	◊ BOTI	Q800F0	60 ^V	-	-	[75]
¤ Bombina variegata	◊ BVTI	Q800E9	60 ^V	-	-	[75]
¤ Bombina microdeladigitora	◊ BMSI 1	B1P2F8	60 ^V	Trypsin, thrombin	20 (T), 150 (Th) ^b	[76]
¤ Bombina microdeladigitora	◊ BMSI 2	B1P2F9	60 ^V	-	-	[76]
¤ Hyla simplex	Hylaserpin S1	H6SWK9	392	Trypsin,	55 (T),	[77]
	Hylaserpin S1	H6SWK9	392	chymotrypsin	310 (C) ^b	[77]
	◊ Hylaserpin S2	H6SWL0	56 ^V	Trypsin	72 ^b	[77]
¤ Bufo andrewsi	BATI	-	-	Trypsin	14 ^b	[78]
	BATI	-	-	Trypsin	4.6 × 10⁶ (T),	[78]
	Baserpin	-	-	chymotrypsin,	8.9 × 10⁶ (C),	[79]
	Baserpin	-	-	elastase	6.8 × 10⁶ (E) ^f	[79]
¤ Kaloula pulchra hainana	KPHTI	-	-	Trypsin	27 ^c	[80]
¤ Phyllomedusa sauvagii	■ PSKP-1	P83578	58 ^III	Prolyl endopeptidase	124 ± 56 ^g	[81]
¤ Phyllomedusa sauvagii	■ PSKP-2	P83579	58 ^III	-	-	[81]
¤ Phyllomedusa nordestina	PI01	K9N0E2	78 ^III	-	-	[82]
	PI02	K9N1K5	77 ^III	-	-	[82]
	PI03	K9N2T9	53 ^III	-	-	[82]
¤ Agalychnis callidryas	■ ACKTI	I7J523	52 ^III	Trypsin	1.9 ^b	[83]
¤ Dyscophus guineti	♦ Kunitz-type PI	J9UVV9	57 ^III	Trypsin	-	[17]
¤ Kassina senegalensis	♦ KSCI	F8K9Q3	62 ^III	Chymotrypsin	-	[84]
¤ Hyla annectans	♦ Anntoxin	C7AR58	60 ^II	Trypsin	25 ^b	[85]
¤ Odorrana grahami	OGTI	-	17 ^II	Trypsin	400 ^b	[86]
¤ Huia versabilis	HV-BBI	B1VC43	18 ^I	Trypsin	18.8 + 1.8 ^b	[87]
ø Vespa bicolor Fabricius	♦ Bicolin	C0LNR2	54 ^III	Trypsin *, thrombin	550 (T), 26,000 (Th) ^b	[88]
ø Bombus ignitus	♦ Bi-KTI	G3LH89	58 ^III	Plasmin	43.53 ^g, 3.6 ^b	[6]
ø Bombus terrestris	♦ Bt-KTI	D8KY58	58 ^III	Plasmin	2.01 ^b	[89]

* Protease against which the inhibitor showed more potent activity; ^a Number of amino acid residues and disulfide bridges (superscript) of the mature peptide; ^b Measured in terms of K_i value (nM); ^c Measured in terms of inhibitory units (IU)/mg, where 1 IU is the amount of protein that inhibit one unit of enzyme; ^d Measured in terms of K_d value (nM); ^e Unique concentration used (nM); ^f Association rate (k_ass) measured in M⁻¹·s⁻¹; ^g Measured in terms of IC₅₀ value (nM); n.f. means inhibitory activity not found by the authors; - Means data not available in the literature.